Fibrosis occurs when overactive mesenchymal cells generate excess collagen that replaces functional tissue. The skin is a major target of fibrosis resulting from aberrant wound healing, graft-versus-host disease, and au- toimmunity. In some organs, fibrosis is accompanied by the disappearance of lipid-storing cells and replace- ment with pro-fibrotic cells, which suggests a dysregulation of fibroblast-adipocyte cell fate. There is a need for better understanding of the mechanisms of fibrosis because we lack treatment strategies that specifically target the fibrogenic process in most diseases. Elevated platelet-derived growth factor (PDGF) signaling is one of the major drivers of fibroproliferative disorders. There are two receptors, PDGF receptor-? (PDGFR?) and ? (PDGFR?), which have much in common but they are regulated differently and have distinct cellular effects that have not been addressed in the fibrosis literature. Results from the applicant's laboratory point to PDGFR? as the major regulator of fibrosis in mice compared to PDGFR?. More specifically, in dermis-derived progenitor cells, PDGFR? activation blocks adipogenesis and induces the cells to differentiate into pro-fibrotic cells. How- ever, the signaling and transcriptional mechanisms underlying this cell fate switch are unknown. It also remains to be tested whether removal of PDGFR? can improve the tissue response to injury, resulting in less fibrosis and increased regeneration of adipocytes. The hypothesis underlying this project is that PDGFR? regulates the balance of fibrosis versus adipogenesis through the PI3K/Akt/mTOR signaling pathway and a new PDGFR?- regulated transcription factor.
Aim 1 will use dermis-derived mesenchymal progenitor cells (MPCs) as a model system to investigate whether PDGFR?-regulated PI3K/Akt/mTOR signaling is required and sufficient for the cell-fate switch.
Aim 2 will explore the role of a new PDGFR?-regulated transcription factor in fibro-adipogenic fate, using MPCs and mice as model systems, and determine how PDGFR? regulates this new factor in MPCs.
Aim 3 will study dermal wound healing in mice with gain- and loss-of-function mutations in PDGFR? to identify the processes by which PDGFR? regulates scar formation. Mutant cells will be fate mapped to determine how different levels of PDGFR? activity regulate fibro-adipogenic fate in vivo. This work is expected to reveal how the PDGFR? signaling pathway mediates its pro-fibrotic/anti-adipogenic effects on dermal progenitor cells. The discovery of signaling pathways that induce mesenchymal cells towards a profibrotic fate will inform the devel- opment of new therapeutic approaches. Knowledge of how DNA-binding factors regulate MPC fate will have major impact on the understanding of core fibrosis mechanisms. And identifying the specific role of PDGFR? in scar formation will begin to establish it as a molecular target for therapy. The resulting generalizable knowledge about how fibro-adipogenic fate is controlled will improve the restoration of structure and function to damaged organs.

Public Health Relevance

Fibrosis is a common clinical problem where cells generate so much collagen that they replace functional tissue with scar tissue. The goal of this research is to identify genes and signals that regulate the formation of new collagen-producing cells. The results of these studies will lead to generalizable knowledge about cell fate and open a new direction for controlling fibrosis as a means to restore structure and function to damaged organs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR070235-03
Application #
9548556
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Park, Heiyoung
Project Start
2016-09-01
Project End
2021-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Sun, Chengyi; Berry, William L; Olson, Lorin E (2017) PDGFR? controls the balance of stromal and adipogenic cells during adipose tissue organogenesis. Development 144:83-94
He, Chaoyong; Medley, Shayna C; Kim, Jang et al. (2017) STAT1 modulates tissue wasting or overgrowth downstream from PDGFR?. Genes Dev 31:1666-1678